The present invention relates to a formulation and method for the delayed burst release of venlafaxine.
Venlafaxine, 1-[(2-dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol, is an important drug for the treatment of depression. Venlafaxine and the acid salts thereof are disclosed in U.S. Pat. No. 4,535,186, which is hereby incorporated by reference as if fully set forth herein. Venlafaxine hydrochloride is presently administered to adults in compressed tablet form in doses ranging from 75 to 350 mg/day, in divided doses two or three times a day. Currently, in therapeutic dosing with venlafaxine hydrochloride tablets, rapid dissolution results in a rapid increase in blood plasma levels of the active compound shortly after administration followed by a decrease in blood plasma levels over several hours as the active compound is eliminated or metabolized, until subtherapeutic plasma levels are approached after about twelve hours following administration, thus requiring additional dosing with the drug. With the plural daily dosing regimen, the most common side effect is nausea, experienced by about forty five percent of patients under treatment with venlafaxine hydrochloride. Vomiting also occurs in about seventeen percent of the patients.
U.S. Pat. No. 6,274,171, issued on Aug. 14, 2001, describes one attempted solution to the problem of frequent administration of venlafaxine. The disclosure teaches a formulation of spheroids, which is characterized by an outer film coating over a core which contains venlafaxine, and in which both are placed in a hard gelatine capsule. However, administration of this formulation results in blood concentration levels having a distinct peak 4-8 hours after administration.
Clearly, the ability to provide a more even plateau of blood concentration of venlafaxine, and therefore presumably to reduce the occurrence and/or severity of side effects, or even to eliminate such side effects altogether, as well as decreasing the frequency of administration of venlafaxine, would be desirable. In addition, the location of release of venlafaxine may also be problematic, as the above taught formulations clearly result in release occurring to a significant degree in the small intestine, and possibly also in the stomach. Since one of the most significant side effects of venlafaxine is nausea and/or vomiting, indicating gastric distress, clearly release of this active ingredient should not occur in the stomach and/or small intestine.
In U.S. Pat. Nos. 6,403,120 and 6,419,958 there are described and claimed methods and compositions for providing therapeutic blood plasma concentration of venlafaxine over a twenty-four hour period with diminished incidence of nausea and emesis which comprises administering orally to a patient in need thereof, an extended release formulation as defined in said patents. More specifically one finds in both of said patents a specific description and definition of the term xe2x80x9cextended release drug formulationsxe2x80x9d wherein both of said patents provide the same following description and definition:
xe2x80x9cExtended release drug formulations are conventionally produced as compressed tablets by hydrogel tablet technology. To produce these sustained release tablet drug dosage forms, the active ingredient is conventionally compounded with cellulose ethers such as methyl cellulose, ethyl cellulose or hydroxypropylmethylcellulose with or without other excipients and the resulting mixture is pressed into tablets. When the tablets swell upon hydration from moisture in the digestive system, thereby limiting exposure of the active ingredient to moisture. As the cellulose ethers are gradually leached away by moisture, water more deeply penetrates the gel matrix and the active ingredient slowly dissolves and diffuses through the gel, making it available for absorption by the body. An example of such a sustained release dosage form of the analgesic/anti-inflammatory drug etodolac (Lodine(copyright)) appears in U.S. Pat. No. 4,966,768. U.S. Pat. No. 4,389,393 discloses sustained release therapeutic compressed solid unit dose forms of an active ingredient plus a carrier base comprised of a high molecular weight hydroxypropylmethylcellulose, methyl cellulose, sodium carboxymethylcelluslose and or other cellulose ether.xe2x80x9d
Following the above description in said patents there is then presented a further description which states as follows:
xe2x80x9cWhere the production of tablets is not feasible, it is conventional in the drug industry to prepare encapsulated drug formulations which provide extended or sustained release properties. In this situation, the extended release capsule dosage forms may be formulated by mixing the drug with one or more binding agents to form a uniform mixture which is then moistened with water or a solvent such as ethanol to form an extrudable plastic mass from which small diameter, typically of 1 mm, cylinders of drug/matrix are extruded, broken into appropriate lengths and transformed into spheroids using standard spheronization equipment. The spheroids, after drying, may then be film-coated to retard dissolution. The film-coated spheroids may then be placed in pharmaceutically acceptable capsules, such as starch or gelatin capsules, in the quantity needed to obtain the desired therapeutic effect. Spheroids releasing the drug at different rates may be combined in a capsule to obtain desired release rates and blood levels. U.S. Pat. No. 4,138,475 discloses a sustained release pharmaceutical composition consisting of a hard gelatin capsule filled with film-coated spheroids comprised of propanolol in admixture with microcrystalline cellulose wherein the film coating is composed of ethyl cellulose, optionally, with hydroxypropylmethylcellulose and/or a plasticizer.xe2x80x9d
Said patents, having concluded and taught that the preferred solution for obtaining a flattened drug plasma concentration to time profile for extended release of venlafaxine is through use of such extended release drug formulations then specifically described at the top of column three of each of said patents that these formulations are achieved by providing a therapeutically effective amount of venlafaxine hydrochloride in spheroids comprised of venlafaxine, hydrochloride, microcrystalline cellulose and, optionally, hydroxypropylmethylcellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose.
This is also the solution suggested and taught in U.S. Pat. No. 6,274,171 and in U.S. patent applications 2002/0025339 and U.S. 2001/0055612.
In contradistinction to the teachings of all of the above mentioned patents and applications that are based on extended release from microspheroids as a function of the structure and coating thereof, it has now been found that a different and better mechanism of long-term dispersion, e.g. for a period of at least 24 hours, of venlafaxine into the blood stream can be achieved by utilizing a formulation which provides for delayed burst release after a period of at least 3 hours after ingestion to provide for dispersion of venlafaxine into the blood stream through the colon over a period extending over at least 24 hours.
Thus, the present invention provides a method for treating a subject with venlafaxine, comprising administering to the subject a formulation having a therapeutically effective amount of venlafaxine or a pharmaceutically acceptable salt thereof, wherein said formulation provides a delayed burst release after at least three hours resulting in dispersion of the active ingredient mainly through the colon into the blood stream as a result of colon absorption over a period of at least 24 hours.
The delivery system of the present invention also advantageously uses the unique continuous absorption characterizing the colon which results in more flat, consistent concentration levels of the drug in blood. Such an absorption, of course, can significantly contribute to reduce the fluctuations in blood drug concentration thus to prevent the side effects which may appear significantly upon using either immediate or conventional controlled release formulations, thereby improving compliance.
The formulation preferably features a core, over which an outer coating is layered. The core is optionally in the form of a tablet, or capsule or any other solid dosage form. The core preferably comprises a burst controlling agent and a disintegrant.
The outer coating preferably features a water insoluble, hydrophobic polymer, in which particles of a water insoluble but hydrophilic material are embedded. These particles preferably form channels upon contact with water or an aqueous medium, thereby enabling the active ingredient to be released upon the burst of the film coat.
In U.S. Pat. No. 5,840,332 there is described and claimed a gastrointenstinal drug delivery system similar to that utilized in the present invention and the relevant teachings of said patent are incorporated herein by reference. It is to be noted however that the diseases contemplated and taught for treatment with such a formulation were selected from the group consisting of colitis, Crohn""s disease, irritable bowel syndrome, gastritis, pancreatitis, hypertension, angina, arthritis, rheumatoid, arthritis, asthma, arrythmia, local spasmolytic action, ulceration of the mucosa, diarrhea, constipation, polyps, carcinoma, cysts, infectious disorders, and parasitic disorders, and said patent does not teach nor suggest that said formulation would be effective for the administration of a drug such as venlafaxine for the treatment of depression.
Furthermore, as can be seen from comparative Example 11, table 4 and FIG. 11 presented hereinafter, the formulation of the present invention provides a delayed burst release of venlafaxine resulting in a substantially even plasma concentration level of venlafaxine for a period extending over four hours, and a higher AUC (area under the blood concentrationxe2x80x94time curve) when compared with the extended release formulations of venlafaxine presently available on the market and said patent neither teaches nor suggests the surprising characteristics of the venlafaxine formulations of the present invention as demonstrated in said example, table and figure.
Hereinafter, the term xe2x80x9cvenlafaxinexe2x80x9d includes venlafaxine and pharmaceutically acceptable salts thereof, as disclosed for example in U.S. Pat. No. 4,535,186, which was previously incorporated by reference.
The term xe2x80x9chydrophobicxe2x80x9d when applied to a film means, besides its common definition, that the film is relatively non-permeable to water and to water-insoluble compounds. The term xe2x80x9chydrophilicxe2x80x9d when applied to a film means, besides its common definition, that the film is relatively permeable to water and to water-soluble compounds.
The term xe2x80x9csubstantially sustained plateauxe2x80x9d of blood concentration levels as used herein refers to a period of time during which the concentration of venlafaxine in the blood exhibits relatively low variability. The substantially sustained plateau preferably occurs for at least about four hours, but more preferably occurs for a longer period of time of at least about eight hours. By xe2x80x9crelatively low variabilityxe2x80x9d, it is meant that on average, variability is preferably less than about 20% of the blood concentration, and more preferably is less than about 10% of the blood concentration. Similarly, the term xe2x80x9ceven blood concentration levelxe2x80x9d also refers to blood concentrations having relatively low variability as previously described.
The dosage levels of the active ingredient venlafaxine could easily be determined by one of ordinary skill in the art. In particular, effective dosages for venlafaxine are well known in the art.
According to the present invention, there is provided a delayed burst formulation as defined, wherein said formulation preferably provides a substantially sustained plateau of blood concentration level of venlafaxine in the subject, wherein said substantially sustained plateau is present for at least four hours.
Preferably the formulation comprises
(a) a core comprising the venlafaxine, wherein said core includes at least one burst controlling agent and a disintegrant, and wherein said core is formed as a compressed tablet; and
(b) an outer coating over said core, said outer coating comprising a water insoluble hydrophobic carrier and water-insoluble but hydrophilic particulate matter, contained in the carrier, that forms channels in the outer coating, upon contact with water or an aqueous medium wherein said channels imbibe liquid and cause said at least one burst controlling agent to burst said coating, thereby enabling the delayed burst release of venlafaxine through these channels after at least three hours followed by dispersion of venlafaxine into the blood stream mainly through the colon over a period extending over at least twenty-four hours.
More preferably, the core is in the form of one of a tablet or a capsule.
Also more preferably, the burst controlling agent comprises a water insoluble polymer for swelling upon contact with liquid, wherein the polymer does not form a hydrogel.
Most preferably, the water insoluble polymer is selected from the group consisting of an insoluble metal salt of a polysaccharide, a heavily cross-linked polysaccharide, pectin, alginic acid, a vegetable gum, water insoluble starch, micro-crystalline cellulose, water insoluble cross-linked peptide, water insoluble cross-linked protein, water insoluble cross-linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross-linked collagen, and carboxymethyl cellulose. Also most preferably, the water insoluble polymer is calcium pectinate or micro-crystalline cellulose.
Preferably, the core further comprises at least one of an absorption enhancer, a binder, a disintegrant, a hardness enhancing agent, and another excipient. More preferably, the binder is selected from the group consisting of starch, PVP (polyvinyl pyrrolidone), low molecular weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxy methyl cellulose, ethylcellulose, gelatin polyethylene oxide, acacia, dextrin, magnesium aluminum silicate, and polymethacrylates. Also more preferably, the hardness enhancing agent is microcrystalline cellulose.
More preferably, the disintegrant is selected from the group consisting of crospovidone (cross-linked PVP) sodium carboxymethyl starch (sodium starch glycolate), cross-linked sodium carboxymethyl cellulose (Croscarmellose), pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate and a combination thereof.
According to preferred embodiments of the present invention, the core further comprises a buffering agent. Preferably, the buffering agent is selected from the group consisting of an inorganic or organic alkaline salt compound.
Alternatively or additionally, the core further comprises a filler. Preferably, the filler is selected from the group consisting of microcrystalline cellulose, starch, lactitol, lactose, a suitable inorganic calcium salt, sucrose, or a combination thereof.
Also alternatively or additionally, the core further comprises a flow regulating agent. Preferably, the flow regulating agent includes at least one of colloidal silicon dioxide and aluminum silicate.
Preferably, the core further comprises a lubricant. More preferably, the lubricant is selected from the group consisting of stearate salts; stearic acid, talc, sodium stearyl fumarate, and compritol (glycerol behenate), or a combination thereof.
According to other preferred embodiments of the present invention, the water insoluble polymer being used in the film coating composition is relatively rigid. Preferably, the water insoluble polymer is selected from the group consisting of a dimethylaminoethylacrylate/ethylmethacrylate copolymer, the copolymer being based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is approximately 1:20, the polymer corresponding to USP/NF xe2x80x9cAmmonio Methacrylate Copolymer Type Axe2x80x9d, an ethylmethacrylate/chlorotrimethylammoniumethyl methacrylate copolymer, the copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is 1:40, the polymer corresponding to USP/NF xe2x80x9cAmmonio Methacrylate Copolymer Type Bxe2x80x9d, a dimethylaminoethylmethacrylate/methylmethacrylate and butylmethacrylate copolymer, a copolymer based on neutral methacrylic acid esters and dimethylaminoethyl methacrylate esters wherein the polymer is cationic in the presence of acids, an ethylacrylate and methylacrylate/ethylmethacrylate and methyl methylacrylate copolymer, the copolymer being a neutral copolymer based on neutral methacrylic acid and acrylic acid esters, ethylcellulose, shellac, zein, and waxes.
According to still other preferred embodiments of the present invention, the water insoluble particulate matter in the film coating composition is selected from the group consisting of a water insoluble cross-linked polysaccharide, a water insoluble cross-linked protein, a water insoluble cross-linked peptide, water insoluble cross-linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross-linked collagen, a water insoluble cross linked polyacrylic acid, a water insoluble cross-linked cellulose derivatives, water insoluble cross-linked polyvinyl pyrrolidone, micro crystalline cellulose, insoluble starch, micro crystalline starch and a combination thereof.
Preferably, the outer coating further comprises a plasticizer. More preferably, the plasticizer includes at least one of dibutyl sebacate, polyethylene glycol and polypropylene glycol, dibutyl phthalate, diethyl phthalate, triethyl citrate, tributyl citrate, acetylated monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl benzoate, butyl and/or glycol esters of fatty acids, refined mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol and sorbitol or a combination thereof.
Also preferably, the outer coating further comprises a stiffening agent. More preferably, the stiffening agent is cetyl alcohol.
Preferably, the outer coating further comprises at least one of a wetting agent, a suspending agent, and a dispersing agent, or a combination thereof. More preferably, the wetting agent is selected from the group consisting of poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, and docusate sodium. Also more preferably, the suspending agent is selected from the group consisting of alginic acid, bentonite, carbomer, carboxymethylcellulose, carboxymethylcellulose calcium, hydroxyethylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin, gelatin, guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol, medium chain triglycerides, methylcellulose, polyoxyethylene sorbitan fatty acid esters (polysorbates), ppvidone (PVP), propylene glycol alginate, sodium alginate, sorbitan fatty acid esters, and tragacanth. Most preferably, the dispersing agent is selected from the group consisting of poloxamer, polyoxyethylene sorbitan fatty acid esters (polysorbates) and sorbitan fatty acid esters.
According to other preferred embodiments of the present invention, there is provided a method for a treating a subject with venlafaxine, comprising: administering to the subject a formulation having a therapeutically effective amount of venlafaxine or a pharmaceutically acceptable salt thereof, Preferably, the formulation comprises: (a) a core containing the venlafaxine, the core comprising a water insoluble, swellable polymer, and a disintegrant; and (b) a coating comprising a water insoluble, hydrophobic polymer and water-insoluble but hydrophilic particulate matter embedded in the polymer, for forming channels in the outer coating, upon contact with water or an aqueous medium wherein said channels imbibe liquid and cause at least one burst controlling agent to burst the coating, thereby releasing venlafaxine; wherein an amount of the disintegrant and the water insoluble swellable polymer is selected such that the core releases venlafaxine in a manner providing a substantially even blood concentration level of venlafaxine for a period extending over at least about four hours.
According to still another embodiment of the present invention, there is provided a method for providing enhanced bioavailability of venlafaxine in a subject, comprising: administering to the subject a formulation having a therapeutically effective amount of venlafaxine or a pharmaceutically acceptable salt thereof, wherein the formulation provides a substantially sustained plateau of blood concentration level of venlafaxine in the subject, the combination of preferential release in the colon and substantially sustained plateau of blood concentration level resulting in enhanced bioavailability of venlafaxine.
According to another embodiment of the present invention, there is provided a formulation for release of venlafaxine in the colon of a subject, comprising: (a) a core that comprises the venlafaxine, wherein the core includes at least one burst controlling agent and a disintegrant, and wherein the core is formed as a compressed tablet; and (b) an outer coating over the core, the outer coating comprising a water insoluble hydrophobic carrier and water-insoluble but hydrophilic particulate matter, contained in the carrier, for forming channels in the outer coating, upon contact with water or an aqueous medium, wherein said channels imbibe liquid and cause the at least one burst controlling agent to burst the coating, thereby releasing venlafaxine in a delayed burst release after at least three hours followed by dispersion of venlafaxine through the colon into the blood stream over a period extending over at least twenty-four hours.